Alzheimer's disease is a brain degenerataive process involving cognition impairments and partial or total loss of memory. Studies in rodents and humans have shown that drugs that stimulate acethylcholine receptors either directly (e.g., arecoline) or indirectly by inhibition of acetylcholinesterase (AChE) (e.g., physostigmine) can enhance performance. However, the toxicity, unpleasant peripheral side effects and short duration of action interfere with their therapeutic uses. Thus, no effective therapy exists for Alzheimer's disease. This collaborative grant application is for the design, synthesis and evaluation of new cholinergics and anticholinergics as potential agents for the treatment of Alzheimer's patients. In order to obtain a broad pharmacological profile, newly synthesized compounds will be evaluated in in vitro and receptor binding assays designed to measure muscarinic agonist and antagonist activities and selectivities. Pharmacological studies will include: 1) agonist and antagonist activity in: a) intestinal smooth muscle; b) vascular smooth muscle (endothelium intact); c) cardiac muscle - guinea pig atria; d) guinea pig myenteric plexus (effects on agonist and electrically induced release of acetylcholine); e) amylase release; and 2) radioligand binding competitive experiments against (3H)quinuclidinyl benzilate, (3H)N-methyl-scopolamine and (3H)pirenzipine in: a) smooth muscle - gut; b) cardiac muscle; c) cerebral cortex; d) cerebellum; e) salivary gland. The development of new, more effective, selective and less toxic cholinergic and anticholinergic drugs is of interest due to the possible therapeutic exploitation of the cholinergic hypothesis of Alzheimer's disease.